Certain substituted ureas, and related compounds, the aminopyridines, have been demonstrated as having a wide variety of practical applications. For example, U.S. Pat. No. 2,344,934 describes quarternary nitrogen condensation products of methylol urea ethers which are useful in creaseproofing and waterproofing textile fibers. A wide range of related compounds such as dipyridyl derivatives (U.S. Pat. No. 2,973,528), alpha-halo-formamidines (U.S. Pat. No. 3,084,192), 3-aminopyridines (U.S. Pat. No. 3,547,935), amidines (U.S. Pat. No. 3,074,955), and pyridyl ureas (U.S. Pat. Nos. 3,293,257; 3,330,641) have proven useful as herbicides or plant growth regulators.
Similar compounds have also proven to have many pharmaceutical applications. Pyridyl ureas may be useful as histamine receptor inhibitors (U.S. Pat. Nos. 3,932,427; 4,215,125) or gastric secretion inhibitors (U.S. Pat. No. 4,203,988). Certain other pyridine derivatives exhibit diuretic activities (U.S. Pat. No. 4,244,950) or broncho-spasmolytic action (U.S. Pat. No. 4,289,765).
Of particular interest are the aminopyridines which show a wide variety of neural effects, such as facilitating chemical transmission at central synapses, autonomic ganglia and neuromuscular junctions. Certain of these compounds may also be utilized in effecting conduction in excitable membranes and increasing muscle contractibility (Bowman and Savage, Rev. in Pure and Appl. Pharmacol. Sci., 2:317, 1981). Among the most important of the practical applications of this activity is their potential use as anti-curare agents.
In practice, nondepolarizing compounds such as curare and its derivatives, for example, d-tubocurarine and pancuronium are routinely utilized to achieve muscular relaxation during surgery. Antagonism of the neuromuscular block effected by these curare compounds has generally been accomplished by the administration of anticholinesterases such as neostigmine methylsulfate (Prostigmine) or pyridostigmine bromide (Mestinon). Unfortunately, anticholinesterases generally cause such undesirable muscarinic side effects as cardiac arrhythmias, bradycardia, atrio-ventricular block, bronchiolar constriction and increased intestinal motility, and must be administered simultaneously with antimuscarinic (anticholinergic) agents such as atropine sulfate or glycopyrrolate. Additionally, anticholinesterases have no antagonistic effect on the neuromuscular blocks effected by certain antibiotics, such as aminoglycosides, lincomycin, spectinomycin and polypeptide-type antibiotics, local anesthetics, low Ca.sup.++ or high Mg.sup.++ concentration in extracellular fluid or botulinum poisoning.
Availability of a compound with potential for broad application as a neuromuscular block antagonist, and which also has none of the unpleasant anticholinesterase side effects, is clearly desirable. Aminopyridines, and in particular, 4-aminopyridine (4-AP), have no anticholinesterase activity and have been shown to not only reverse the side effects of clinically used muscule relaxants, but also antagonize the effects of the other neuromuscular blocks listed above (Bowman and Savage, Rev. in Pure and Appl. Pharmacol. Sci. 2:317, 1981; Agoston, et al., Br. J. Anaesth. 50:383, 1978). Unfortunately, the use of 4-AP is accompanied by such undesirable side effects as elevated blood pressure, anxiety, insomnia, and a level of central nervous system stimulation which may manifest itself ultimately in convulsions. Therefore, its utility as a therapeutic agent is clearly very limited (Marshall, Advances in the Biosciences 35:145, 1982).
Surprisingly, recent experimentation has shown that certain aminopyridine derivatives, in particular, substituted ureas, exhibit potency as neuromuscular block antagonists equivalent to or even greater than that of known aminopyridines. These compounds, similarly to 4-AP, do not require concurrent use of anticholinergic drugs which may have the above-mentioned dangerous side effects. The compounds of the present invention also represent a significant improvement over previous compounds in that they do not exhibit the unpleasant, an often lethal, central nervous system side effects which may accompany administration of substances such as 4-AP.